ARTICLE

doi:10.1038/nature13735

Multifunctional organoboron compounds for scalable natural product synthesis Fanke Meng1, Kevin P. McGrath1 & Amir H. Hoveyda1

Efficient catalytic reactions that can generate C–C bonds enantioselectively, and ones that can produce trisubstituted alkenes diastereoselectively, are central to research in organic chemistry. Transformations that accomplish these two tasks simultaneously are in high demand, particularly if the catalysts, substrates and reagents are inexpensive and if the reaction conditions are mild. Here we report a facile multicomponent catalytic process that begins with a chemoselective, site-selective and diastereoselective copper–boron addition to a monosubstituted allene; the resulting boron-substituted organocopper intermediates then participate in a similarly selective allylic substitution. The products, which contain a stereogenic carbon centre, a monosubstituted alkene and an easily functionalizable Z-trisubstituted alkenylboron group, are obtained in up to 89 per cent yield, with more than 98 per cent branch-selectivity and stereoselectivity and an enantiomeric ratio greater than 99:1. The copper-based catalyst is derived from a robust heterocyclic salt that can be prepared in multigram quantities from inexpensive starting materials and without costly purification procedures. The utility of the approach is demonstrated through enantioselective synthesis of gram quantities of two natural products, namely rottnestol and herboxidiene (also known as GEX1A).

Enantioselective processes where a catalyst unites a pair of starting materials and then induces the resulting species to react with a third substrate are sought-after in chemistry1,2. Pathways that involve difficult-to-access intermediates and products then become feasible, and wasteful and costly procedures for isolation and/or purification of sensitive reagents become unnecessary3. Rare instances of such multicomponent processes can be found in phosphine–Ir or Ru-catalysed enantioselective reductive fusion of hydrogen, unsaturated hydrocarbons and carbonyl or imine compounds4,5. An unprecedented degree of complexity would result if a multitasking catalyst were to promote several transformations that are each selective on multiple levels, with the final product bearing the marks of every single discriminatory event; a representative pathway is shown in Fig. 1a.

Multicomponent synthesis of complex fragments Boron-substituted alkenes are widely used multipurpose moieties. Singlecatalyst/multisubstrate transformations that deliver multifunctional unsaturated organoboron compounds are therefore of great interest. In the first phase of our studies (Fig. 1b), we found that chemoselective addition of (phosphine)Cu–B(pin) (here B(pin) 5 (pinacolato)boron), derived from reaction of an in situ generated (phosphine)Cu–alkoxide with B2(pin)2, to a monosubstituted allene (versus an aldehyde) affords 2-B(pin)substituted allylcopper complex i, which then reacts with an aldehyde (versus an allene) to afford homoallylic alkoxide iii. An assortment of aldol-type products were obtained after oxidative treatment in up to .99:1 diastereomeric ratio (d.r.) and 97:3 enantiomeric ratio (e.r.)6. In contrast, transformations with N-heterocyclic carbene (NHC) complexes of copper, while efficient, generated racemic products. The above reactions give 1,1-disubstituted alkenylboron units because of a second-stage c addition (ii), which causes the loss of an important attribute of the initially formed intermediate (i): a stereochemically defined and modifiable trisubstituted olefin. A multicomponent catalytic enantioselective process that preserves the trisubstituted alkenylboron group would have higher value. We thus envisioned a transformation involving chemo-, site- and stereoselective Cu–B(pin) addition to an allenyl 1

substrate followed by chemo- and site-selective (branched versus linear) cross-coupling of the resulting allylcopper species through enantioselective allylic substitution (EAS). The envisioned catalytic sequence would furnish multifunctional organoboron products v by a single operation; this would be in contrast to the existing strategies where each functional unit must be installed individually through extended and less efficient sequences7,8 (for a complete bibliography, see Supplementary Information). Such a process would be a significant addition to an important but limited group of catalytic allyl–allyl reactions. Site- and enantioselective incorporation of allyl groups through catalytic EAS has been confined to simple fragments introduced via allylboron9, allylmagnesium10 or allylic alcohol11 compounds (see Supplementary Information for a complete bibliography). The expected organoboron products (v, Fig. 1b) are rich in adaptable moieties. A stereogenic centre could be formed in the homoallylic position of a stereochemically defined trisubstituted alkenylboron unit that may be converted to other E- or Z-trisubstituted olefins. For instance, conversion of the C–B(pin) of v to a C–C bond with inversion of stereochemistry would deliver vi, which is a functional group found in numerous biologically active molecules; a notable case corresponds to a segment of immunosuppressive agent FK-50612 (compare highlighted fragment in Fig. 1c). Efficient and stereoselective synthesis of such trisubstituted olefin-containing fragments remains a difficult problem. In previous efforts either the undesired Z olefin was removed from a near-equal mixture of isomers13,14, or modification of a terminal alkyne by relatively lengthy routes was required15. The terminal olefin of the products is an asset as well: it would provide the opportunity for many types of modifications. One example entails conversion to an E,E-diene by sequential catalytic cross-metathesis with vinyl–B(pin)16 and cross-coupling (Fig. 1c)17, generating a fragment that is common to several biologically active natural products. The highlighted segments in nafuredin (NADHfumarate reductase inhibitor18,19), milbemycin b3 (insecticidal20), rottnestol (member of a family of antibiotics21) and herboxidiene (phytotoxic, anti-tumour22) are representative.

Department of Chemistry, Merkert Chemistry Center, Boston College, Chestnut Hill, Massachusetts 02467, USA. 1 8 S E P T E M B E R 2 0 1 4 | VO L 5 1 3 | N AT U R E | 3 6 7

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RESEARCH ARTICLE a

Catalytic cycle for a multicomponent process with each step inducing multiple selectivities that are preserved within product structure Substrate 1

Product

Substrate 2 Reagent Catalyst

Ideally, contains the mark of all 6 points of selectivity

Reagent

Catalyst Catalyst

Faster

5. Site selectivity, 6. Stereoselectivity

2. Site selectivity, 3. Stereoselectivity

Substrate 1

Faster

Substrate 2

1. Chemoselectivity

4. Chemoselectivity

Slower

Slower

Substrate 2

Catalyst

Substrate 1

b

Multicomponent catalytic methods for preparation and in situ use of alkenylboron compounds Catalytic Cu–B(pin) addition/ enantioselective aldehyde addition (EAA) B2(pin)2

R

(pin)B–Ot-Bu

(L)Cu–B(pin) G

R

OPO(OEt)2

G R (pin)B

G

ii

iii

α addition

G

OB(pin)

G

Cu(L)

Catalytic Cu–B(pin) addition/ enantioselective allylic substitution (EAS)

c

H

L = phosphines

G Cu(L) B(pin) i Used in situ not isolated or purified

•

γ addition H (pin)B (L)Cu O R

O

(L)Cu–Ot-Bu

Optimal chiral catalyst? (L = ?)

(pin)B

(pin)B

R iv

Reductive elimination

R v

Representative natural products that may be prepared through the new multicomponent process G Stereogenic centre

Z-trisubstituted alkenyl–B(pin)

B(pin) C–B(pin)

Me–C

Catalytic cross-metathesis;

G

With inversion Me Functionalizable terminal olefin of stereochemistry v

(pin)B

Me vi

G1

G

G1 halide Catalytic cross-coupling

Me

Me

Me vii

O HO

O

Me MeO

Me

MeO H

Me

O

Me O

O

Et Me

O

Me

Me

Me

Me

Nafuredin

OH

HO

Me

O

N

Me OH

O

O

O Me

Me

OH

Me Milbemycin β3

OH

Me

Rottnestol

OMe Me

Me Me

O

Me

O

O FK-506

O

Me

OH

OMe

O O CO2H

Me

Me

Me

Me Me

OH

Herboxidiene/GEX1A

Figure 1 | Multicomponent catalytic enantioselective generation of alkenylboron compounds. a, The general scheme for a multicomponent catalytic cycle involving a reagent and two substrates might be envisioned to proceed by a sequence entailing multiple selectivity issues. Ideally, all points of selectivity would be retained. b, Catalytic stereoselective generation of an alkenyl–B(pin) intermediate (i), which might react in situ site-, diastereo- and enantioselectively with an aldehyde or an allylic phosphate to generate valuable

multifunctional products. In the second proposed sequence, each point of selectivity, especially the trisubstituted alkene, would be preserved within the final structure. c, Sequential catalytic Cu–B(pin) addition/enantioselective allylic substitution, affording products represented by v, constitutes an attractive strategy for synthesis of biologically active compounds. NHC, N-heterocyclic carbene; B(pin), (pinacolato)boron; G, functional group.

Catalyst identification and method development

To identify conditions that would deliver 3a in favour of 1,1disubstituted alkenyl–B(pin) 4, achiral 5 or diene 6 (Table 1), we selected the reaction involving allene 1a and allylic phosphate 2a. We soon found that, unlike reactions with aldehydes6 (Fig. 1b), a phosphine–Cu complex is ineffective (for example, with PCy3 and 725, entries 1 and 2, Table 1), and bis-phosphine-derived catalysts cause only the allylic phosphate to be consumed (for example, with complex derived from 8, entry 3). That is, unlike the reactions involving aldehydes, monosubstituted allenes fail to compete with allylic phosphates when bis-phosphines serve as ligands. These observations substantiated our initial concerns regarding the presence of two types of electrophilic olefin. We then made the unexpected discovery that, in further contrast to carbonyl additions, an NHC–Cu complex can guide the catalytic cycle along the desired path (Table 1). The NHC–Cu species derived from

Successful implementation of the aforementioned plan demands high chemoselectivity despite the involvement of two C–C p bonds (that is, Cu–B(pin) addition to allene versus allylic phosphate). Monosubstituted allenes23 as well as allylic carbonates24 have indeed been shown to undergo efficient reactions with copper–boron complexes. Allenes are comparatively unhindered and might react with a Cu–B(pin) complex more readily, but the Lewis basic phosphate can associate with a transition metal to set off an undesirable sequence of events. Another strategic element is that reaction of the allylcopper intermediate with the allylic phosphate must be followed by a facile reductive elimination (iv, Fig. 1b); this way, the trisubstituted alkenylboron unit would be retained and the chiral, branched product isomers would be formed preferentially (that is, 3a favoured over 4–6; see Table 1). 3 6 8 | N AT U R E | VO L 5 1 3 | 1 8 S E P T E M B E R 2 0 1 4

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ARTICLE RESEARCH Table 1 | Examination of copper complexes as catalysts for sequential Cu–B(pin) addition/EAS The representative process:

TBSO

(pin)B

TBSO Ph

5.0 mol% ligand, 5.0 mol% CuCl

1a (1.2 equiv.)

2a Reacts readily in the absence of allene (see text)

Ph 4 addition, SN2′ (branched) disubstituted alkene, chiral

TBSO

1.5 equiv. KOt-Bu, 1.2 equiv. B2(pin)2, THF, 22 °C, 18 h

OPO(OEt) 2

Ph

3a addition, SN2′ (branched) trisubstituted alkene, chiral

•

B(pin)

TBSO

B(pin)

TBSO

Ph

Ph B(pin) 5 addition, SN2 (linear) trisubstituted alkene, achiral

6 addition, SN2 (linear) disubstituted alkene, chiral

The phosphine ligands and NHC precursors: O

O

O

PNMe 2 O

7

PPh 2

O

N

+ NMes

OH

Ph

N

– PF6 + NMes

OH 12a

MesN

8

O

– PF6 i-Pr

– Cl + NMes

PPh 2

9b

t-Bu

PF 6 + NMes

N

Ph R N OH

12c

+ N

Ph –Cl + NMes

Ph SO 3

10

HO

–

OH 12b

N

+ NMes

MesN

9a

Ph

–

Ph BF4

Ph

Et – PF 6

Ph

Ph + NMes

N

11

N

+ N

Et

OH i-Pr

12d

12e

i-Pr

– PF 6

Entry number

Ligand or ligand precursor

Conversion (%)*; yield of 3a (%){

Site selectivity (3a:4:5:6)*

Z:E*

Enantiomeric ratio for 3a{

1 2 3 4 5 6 7 8 9 10 11 12

PCy3 7 8 9a 9b 10 11 12a 12b 12c 12d 12e

,2; NA ,2; NA .98; ,2 ,98; 81 40:,2 .98; 36 .98; ,2 .98; 67 .98; 74 .98; 72 .98; 80 .98; 77

NA NA NA .98:,2:,2:,2 NA .98:,2:,2:,2 NA .98:,2:,2:,2 .98:,2:,2:,2 .98:,2:,2:,2 .98:,2:,2:,2 .98:,2:,2:,2

NA NA NA .98:2 NA .98:2 NA .98:2 .98:2 .98:2 .98:2 .98:2

NA NA NA NA NA 22:78 (R:S) NA 89:11 (R:S) 93:7 (R:S) 85:15 (R:S) 94:6 (R:S) 92:8 (R:S)

Reactions were carried out under N2 atmosphere; see Supplementary Information for details. NA, not applicable; Mes, 2,4,6-Me3-C6H2. * Conversion, site selectivity and Z:E ratios were determined by analysis of 400 MHz 1H NMR spectra; variance of values is estimated to be ,62%. { Yield of purified products. { Enantiomeric ratio values were determined by HPLC analysis; variance of values is estimated to be ,61%. See Supplementary Information for details.

aryl-substituted heterocyclic salt 9a (entry 4) afforded 3a as the major component (81% yield); the alternative alkenylboron-containing products 4, 5 or 6 were not detected (,2%); the complete site (branch) selectivity was equally surprising. Conversely, with enantiomerically pure 9b (entry 5), 3a was isolated in trace amounts, and reactions involving chiral salts 1026 and 1127 either produced 3a in low yield (compare phenol 10, entry 6) or none at all (compare sulphonate 11, entry 7). Investigation of enantiomerically pure NHC precursors bearing an N-aryl and an N-alkyl group led us to establish that reaction with aminoalcohol-derived 12a28 (entry 8, Table 1) affords 3a in 67% yield, .98% SN29 selectivity and 89:11 e.r. Follow-up studies revealed that enantioselectivity can be sensitive to the substituent at the stereogenic centre of the chiral catalyst (entries 8–10, Table 1). Additional modification revealed that 12d is precursor to a more efficient (80% yield; entry 11) and enantioselective catalyst (94:6 e.r.). Incorporation of larger N-aryl substituents did not lead to any improvement (compare 12e, entry 12). The method can be used to prepare a range of multifunctional organoboron compounds in high selectivity (Fig. 2a). The requisite imidazolinium salt 12d, an air-stable solid, can be prepared in multigram quantities by a modified version of a reported procedure28; the necessary reagents, including either enantiomeric form of phenylglycinol, can be bought at low cost. Allylic phosphates bearing sterically hindered substituents (3b, c), halogenated aryl groups (3d, e) or an alkyl unit (13) are suitable substrates. Although NHC–Cu–B(pin) complexes react readily with b-alkylstyrenes29, additions to an allene/EAS occur more readily (14). Allenes that contain other modifiable groups, such as an alkyne (15), an amine (16), or an amide (17 or 19) may be used. As the outcomes of the transformations expected to generate amides 17–19 indicate, a Lewis basic group, depending on its distance from the allene site, can alter reaction rates. Unsubstituted allene was used to access 1,1-disubstituted alkenyl– B(pin) 20 in 89% yield, .98% branch selectivity and 97:3 e.r. Catalytic

cross-coupling reactions with readily accessible aryl halides proceed with retention of stereochemistry to generate trisubstituted alkenes (21–23, Fig. 2b).

Origins of high efficiency and selectivity The challenge of designing a multicomponent process is in identifying a catalyst that can clear several efficiency and selectivity hurdles before reaching the finish line and starting again. Key attributes of the optimal NHC–Cu complex (derived from 12d) are discussed below. Chemoselectivity and efficiency The difference between percentage conversion and yield of 3a with certain Cu complexes (Table 1) signals a breakdown in chemoselectivity: competitive Cu–B addition to 2a (versus allene 1a) leads to formation of by-products. Hence, it appears that the less Lewis basic and sterically demanding phosphine-based systems (for example, 8, Table 1), which are distinct from those of NHC ligands30,31, allow the phosphate to associate and react more readily. The pathway that hampers the transformations of the less effective NHC–Cu complexes is more tractable. Allylic substitution of a B(pin) group with 2a produces a branched allylboron intermediate (24, Fig. 3a) that can be converted to the corresponding allylcopper species (25), which then reacts with another molecule of allylic phosphate 2a to form 1,5-diene 26. Indeed, without the allene, the NHC– Cu complexes catalyse the formation of diene 26 efficiently (for example, 53% yield for 9a, 76% yield for 11 and 50% yield for 12d). Similar generation of an allylcopper might be inefficient with the Cu centre of a bisphosphine complex, which is probably less Lewis acidic as a result of its weaker two-electron donor ligand (versus an NHC)32, causing the allylboronate compound to react in other ways. Comparison of the transformations performed with NHC–Cu complexes derived from 9c–f (Fig. 3b) indicates that the proper balance 1 8 S E P T E M B E R 2 0 1 4 | VO L 5 1 3 | N AT U R E | 3 6 9

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RESEARCH ARTICLE a

An efficient, practical and selective multicomponent NHC–Cu-catalysed process Ph

Et – PF

6

Et OH R-12d

•

TBSO

5.0 mol% CuCl, 1.5 equiv. KOt-Bu, 1.2 equiv. B2(pin) 2,

1a

TBSO

+ N

N

5.0 mol%

(pin)B

THF, 4 °C, 24 h Ph 2a

TBSO

TBSO

(pin)B

3b at 22 °C, 18 h: >98% conv., 72% yield, >98% branched, >98% Z, >99:1 e.r.

(pin)B

(pin)B Br 3d at 4 °C, 24 h: >98% conv., 68% yield, >98% branched, >98% Z, 94:6 e.r.

3c at 22 °C, 18 h: >98% conv., 80% yield, >98% branched, >98% Z, 95:5 e.r.

TBSO

TBSO

TBSO

Me

(pin)B

Ph

3a >98% conv., 75% yield, >98% branched, >98% Z, 97:3 e.r.

OPO(OEt) 2

Cl 3e at 4 °C, 24 h: >98% conv., 75% yield, >98% branched, >98% Z, 92:8 e.r.

Ph Bn 2N t-BuMe 2 Si

(pin)B (pin)B Ph 13 at 4 °C, 24 h: >98% conv., 84% yield, >98% branched, >98% Z, 94:6 e.r.

Me

Ph

(pin)B

14 at 22 °C, 18 h: >98% conv., 77% yield, >98% branched, >98% Z, 99:1 e.r.

OMe N

O Me

O (pin)B

N OMe

Ph

Ph

15 at 22 °C, 18 h: >98% conv., 70% yield, >98% branched, >98% Z, 96:4 e.r.

Me

(pin)B

OMe N H

O (pin)B

Ph

(pin)B

H

Ph

(pin)B 17 at 22 °C, 18 h: >98% conv., 83% yield, >98% branched, >98% Z, 94:6 e.r.

b

18 at 22 °C, 18 h: 98% conv., 73% yield, >98% branched, >98% Z, 99:1 e.r.

19 at 22 °C, 18 h: 87% conv., 74% yield, >98% branched, >98% Z, 95:5 e.r.

Ph

20 at 22 °C, 18 h: >98% conv., 89% yield, >98% branched, 97:3 e.r.

Representative catalytic cross-coupling functionalization of the trisubstituted alkenyl–B(pin) products TBSO

2.0 mol% Pd2(dba)3, 4.0 mol% S-Phos (pin)B 3a

Ph

1.5 equiv. 2-bromopyridine, THF:3.0 M NaOH (3:1), 60 °C, 18 h With >98% retention of stereochemistry

TBSO

TBSO

TBSO

N

Ph

Ph N

21 77% yield, >98% E

N

22 74% yield, >98% E

Ph

N S

23 83% yield, >98% E

Figure 2 | Catalytic chemo-, site- and enantioselective multicomponent reactions. a, Transformations are promoted by NHC–Cu complexes generated in situ from 12d, which can be easily prepared from inexpensive starting materials on a multigram scale in ,50% overall yield. Transformations proceed with 5.0 mol% catalyst at 4–22 uC and are complete in 18–24 h to deliver the desired products in .98% Z, SN29 and chemoselectivity and 92:8 to .99:1

e.r. b, The trisubstituted alkenyl–B(pin) obtained with complete Z selectivity can be converted to a variety of trisubstituted E alkenes through catalytic cross-coupling with readily available aryl bromides; all reactions proceed with complete retention of stereochemistry. Conv., conversion; TBS, t-butyldimethylsilyl; dba, dibenzylideneacetone; S-Phos, 2-dicyclohexylphosphino-29,69-dimethoxybiphenyl.

between electronic attributes and size of the heterocyclic ligand is needed if high efficiency and chemoselectivity are to be achieved. The catalyst arising from 9d is too large to promote transformation, whereas the ligands derived from the smaller 9c and 9f contain N-alkyl units (versus N-aryl) and are therefore too nucleophilic to facilitate the desired succession of events. Imidazolinium salt 9e delivers an NHC–Cu complex that is small enough to promote reaction without being too diminutive or overly nucleophilic to promote Cu–B(pin) addition to the allylic phosphate. The complex resulting from 10 (.98% conversion, 36% yield of 3a; entry 6, Table 1) in all probability serves as a monodentate ligand that contains an N-mesityl and a smaller ortho-substituted N-aryl moiety, rendering it less selective (see below). The bidentate Cu catalyst arising from 11 is probably the only instance of a bidentate complex formed in the screening studies (detailed below); the cuprate species possesses higher-energy Cu d-electrons that are more suitable for interacting with the lowerlying p* orbital of an allylic phosphate (versus an allene)33, facilitating the undesired allylic substitution of a B(pin) unit (low chemoselectivity).

Branch- and enantioselectivity Chiral heterocyclic ligands (for example, 10, 11, 12a–e) with a chelating group commonly serve as precursors to bidentate NHC–Cu systems (that is, cuprate complexes). However, the resulting Cu–O tether can rupture through reaction with B2(pin)2, revealing a monodentate complex that carries a neutral metal centre34. For two reasons we did not initially think that such a cleavage would take place with Cu complexes resulting from 12a–e. First, exceptional SN29 selectivity is usually observed with reactions of organoboron compounds that are promoted by bidentate NHC–Cu catalysts34,35; this preference may be attributed to rapid reductive elimination of the Cu(III) intermediate33 so that substantial steric hindrance can be relieved (compare the top pathway available to II in Fig. 3d). The less sterically demanding monodentate complexes, on the other hand, generate achiral linear isomers either preferentially34 or to a significant degree35. Second, high enantioselectivities have been observed with catalysts that contain a chiral NHC ligand that is either bidentate (for example, 11 in Table 1)28, or monodentate (for example, 9b) but with conformationally

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ARTICLE RESEARCH a

The major competitive pathway in NHC–Cu-catalysed reactions B(pin)

(Table 1) Ph

OPO(OEt) 2

KOt-Bu

Ph

2a

(NHC)Cu

24

2a

Cu(NHC)

Ph

Ot-Bu

Ph

25

b

Ph

26

KOt-Bu

+

(NHC)Cu–OPO(OEt) 2

Additional findings relevant to efficiency Same conditions as shown in Table 1 1a + 2a + – NCy BF4

CyN

DippN

+ – NMes Cl

MesN

9d 98% conv., 32% yield, >98% SN2′

c

3a + various byproducts + – NDipp Cl

9e >98% conv., 54% yield, >98% SN2′

Same conditions as shown in Table 1

Et Ph

+ N

N

Et

– PF

6

Ph

N

+ N

–

R-3a + S-3a

PF6

Me

+ N

N

–

PF6

HO

Et 12g >98% conv., 69% yield, >98% 3a, >98% SN2′, 51:49 e.r.

Et 12f >98% conv., 74% yield, >98% 3a, >98% SN2′, 91:9 e.r.

Me 12h >98% conv., 53% yield, >98% 3a, >98% SN2′, 51:49 e.r.

Stereochemical models based on DFT calculations Fast reductive elimination O

B

N

N

N

O H

III

I

Cu

Cu

O

O

P

N

N (pin)BO

I

O

O P

O

B(pin) Ph

reductive elimination

II

N

Cu

-allyl isomerization,

O

B O H H

OPO(OMe) 2 H

B O Ph O

O I

O

H Ph (pin)B viii Branched isomer, major enantiomer

N

(pin)BO H

H

B O O

O

Ph

MeO

TBSO

O

9f >98% conv., 17% yield, >98% SN2′

Additional findings relevant to enantioselectivity 1a + 2a

d

+ – NMe Cl

MeN

ix Linear isomer

N

H

H

Steric repulsion

III

Cu

Minor enantiomer

OPO(OMe) 2

Ph

O B O

Steric repulsion

O B

O IV

III

e

Effect of internal chelation on reactivity O Me

N

MeO

N OMe Cu(L n) B(pin) x

Me

N

(pin)BO H

N O Cu (L n) B(pin) xi

Inhibiting allylic phosphate binding (compare 18 in Fig.2a)

Cu

H

O B O O

O

P O

O V

Figure 3 | Origins of high efficiency and selectivity. a, Low efficiency with some NHC–Cu-catalysed reactions is due to a competitive pathway arising from undesirable chemoselectivity. b, The efficiency of the multicomponent process hinges on the catalyst possessing the appropriate steric and electronic attributes. c, Modification of the chiral NHC ligand indicates that the optimal Cu-based catalyst is likely to be a monodentate complex with an N-alkyl side chain containing the sole stereogenic centre. d, DFT calculations point to a

mode of transformation (I) leading to the major enantiomer (versus III). The uniformly exceptional branch or SN29 selectivity (versus linear or SN2), despite the involvement of a neutral monodentate NHC–Cu catalyst, might be due to steric facilitation of the reductive elimination step (versus p-allyl formation) via II and IV. e, Evidence for the importance of Cu–phosphate chelation to reaction efficiency. Dipp, 2,6-(i-Pr)2C6H3; TBS, (t-Bu)Me2Si.

constraining stereogenic centres36,37, or both24,34,35. High enantioselectivity without bidentate ligation and/or conformationally restricting substituents is unusual, since it must originate from a single stereogenic centre within the conformationally flexible arm of a C1-symmetric NHC ligand. Nevertheless, such a scenario became irrefutable when we found that reaction with silyl ether 12f (Fig. 3c) proceeds with nearly identical efficiency and selectivity as when 12d is used. (We were unable to prepare and examine an authentic sample of the boronate derivative; similar results were obtained with the corresponding tert-butyldiphenylsilyl ether analogue of 12f.) Additionally, with methyl ether 12g (Fig. 3c), enantioselectivity was all but completely eroded. Stereoselectivity is thus likely to be induced by the large B(pin)-substituted chiral appendage, formed through reaction of B2(pin)2 with the Cu–O bond and emulated by the silyl ether in 12f. Calculations through the use of density functional theory (DFT) point to transition structure I as the source of the major product enantiomer (Fig. 3d; see Supplementary Information for details of all calculations).

The allylic phosphate occupies two sites of the tetrahedral Cu(I) complex to generate a square planar Cu(III) species that undergoes reductive elimination via II to give viii (versus ix). The P5ORCu coordination facilitates the association of the allylic phosphate with the sterically demanding NHC–Cu–allyl complex; this picture is supported by the variations in reaction efficiency observed for the transformations involving products 17–19 (Fig. 2a). In the case of 18 (,2% conversion), the Lewis basic amide carbonyl is properly situated to chelate with the Cu centre in the first intermediate to prevent phosphate chelation (x, Fig. 3e). The ring size in the bidentate complex xi is similar to that found in the oxidative addition precursor V (Fig. 3e). The two-point catalyst/substrate binding enhances the organization of the stereochemistry-determining transition state, generating high stereochemical induction via II. The minor isomer is probably produced via III, wherein the sizeable boronate group can swerve into close contact with the protruding allylic phosphate substituent. The B(pin) moiety of the allyl ligand must either collide with the ethyl substituents of the 1 8 S E P T E M B E R 2 0 1 4 | VO L 5 1 3 | N AT U R E | 3 7 1

©2014 Macmillan Publishers Limited. All rights reserved

RESEARCH ARTICLE NHC’s N-aryl moiety (shown) or induce steric repulsion due to proximity of the B(pin) unit and the NHC side chain. There must therefore be a feature of the catalyst structure that is responsible for C–C bond formation occurring near the chiral arm of the NHC ligand. Molecular models suggest that, because of steric factors, the ortho (ethyl) substituents of the ligand’s N-aryl moiety discourage placement of the allyl fragments in their vicinity. The complete loss of enantioselectivity that results from placement of the groups at the N-aryl moiety’s C3 and C5 positions corroborates the proposed scenario (that is, the derived boronate of NHC precursor 12h, Fig. 3c). Exceptional SN29:SN2 ratios Then there are the exceptional SN29:SN2 ratios despite involvement of a monodentate–Cu complex35,38. This almost certainly originates from the sizeable B(pin) unit of the allyl ligand of the Cu(III) complex; the boronate moiety is absent in the formerly examined EAS reactions with organoboron compounds34,35. The steric repulsion engendered by the sizeable B(pin) group elevates the ground state energy of the Cu(III) intermediate species II (major) and IV (minor), accelerating reductive elimination (to give viii in Fig. 3d) before it can collapse to the p-allyl species (ix in Fig. 3d). DFT calculations support the contention that the presence of the large B(pin) group lowers the activation barrier to reductive elimination (strain release).

Gram-scale total synthesis of rottnestol Synthesis of a complex organic molecule with catalytic multicomponent processes as its central feature would be a clear indicator of the utility of a

such processes, particularly if meaningful quantities of a target molecule were to be secured. We first designed a route to prepare gram quantities of pure rottnestol where every issue of stereochemical control would be addressed by a catalytic transformation. We envisioned using the NHC– Cu-catalysed enantioselective process involving an allylic phosphate for synthesis of the polyene segment, while the carbohydrate moiety would be accessed through a catalytic B2(pin)2/allene/aldehyde fusion (Fig. 4). The synthesis route commenced with the Cu–B(pin) addition/EAS sequence (Fig. 4a). Treatment of monosubstituted allene 1b and methylsubstituted allylic phosphate 2b with 3.0 mol% S-12d and CuCl (Fig. 2) afforded trisubstituted alkenyl–B(pin) 27 in 79% yield, with complete branch and Z selectivity and in 92:8 e.r.; the reaction was performed on two batches of ,1.7 g of 1b, delivering a total of ,4.2 g of the product. Conversion of the C–B(pin) to a C–Me bond was accomplished with complete inversion of stereochemistry (.98% E) through reaction with methyllithium and iodine39, delivering trisubstituted alkene 28 in 91% yield (3.4 g). NHC–Ru-catalysed E-selective cross-metathesis with commercially available vinyl–B(pin)16 in the presence of 5.0 mol% Ru carbene 2940 and formation of the corresponding alkenyl–iodide16 proceeded in 80% overall yield, furnishing ,3.6 g of 30, which was transformed to 1.4 g of triene 31 in three straightforward steps (73% overall yield). To prepare the carbohydrate fragment (Fig. 4b), we adopted an enantioselective reaction involving aldehyde 32, which can be prepared in one step from a commercially available alcohol and four other entities that can also be purchased: methylallene 1c, B2(pin)2, bis-phosphine 33 and CuCl. Silyl protection of the b-hydroxyketone afforded 34 in 75% overall yield (3.4 g through two batches) with complete control of

Enantioselective synthesis of the polyene segment of rottnestol Ph 2(t-Bu)SiO

• Ph 2(t-Bu)SiO Me

1b

With >98% inversion of stereochemistry 6.0 equiv. MeLi, THF, E Ph 2(t-Bu)SiO –78 °C 0 °C, 1.0 h;

Z

3.0 mol% S-12d, 3.0 mol% CuCl

(pin)B Me I 2, MeOH, 27 –78 °C 0 °C, 1.0 h >98% conv., 79% yield, >98% branched, >98% Z, 92:8 e.r. ~1.7 g 1b ~2.1 g (each batch; 2 batches)

1.5 equiv. KOt-Bu, 1.2 equiv. B 2(pin) 2, THF, 22 °C, 18 h

OPO(OEt)2 2b (1.2 equiv.)

Me

Me

28 91% yield (3.4 g), >98% E (inversion) MesN

NHC–Cu-catalysed Cu-boryl addn/EAS

1. 5.0 mol%

NMes

Cl

Ru

Cl I Me Me 31 73% overall yield (1.4 g)

b

Ph 2(t-Bu)SiO

1. (n-Bu) 4NF, THF, 22 °C, 3.0 h

Me

2. py•SO 3, Et( i-Pr) 2N, DMSO, CH2Cl2, 0 °C, 0.5 h 3. Ph 3PCH 3Br, n-BuLi, THF, 0 22 °C, 1.0 h

Oi-Pr

I Me

29

1.2 equiv. vinyl–B(pin), CH2Cl2, reflux, 36 h 2. I 2, NaOH, THF, 22 °C, 2.0 h

30 80% overall yield, >98% E

Enantioselective synthesis of the carbohydrate segment of rottnestol and the final fragment coupling •

Me

1. 3.0 mol% 1c 3.0 equiv.; commercially available

PPh 2 S

PPh 2

33

3.0 mol% CuCl O O

O

Si(t-Bu)Ph 2 O O

O

1. 20 mol% camphorsulphonic acid, MeOH, 22 °C, 1.0 h

OH

O

Me

2. Tf2O, 2,6-lutidine, CH2Cl2, –78 °C, 0.5 h 12 mol% NaOt-Bu, 1.1 equiv. B 2(pin) 2 , Me 3. Me 3SiC≡CLi, THF, DMPU, –78 °C, 1.0 h THF, 4 °C, 12 h; 34 32 4. (n-Bu) 4NF, THF, 22 °C, 12 h NaBO 3 •4H 2O, THF:H 2O (1:1), 22 °C, 1.0 h 75% overall yield, Prepared in one 2. (t-Bu)Ph 2SiCl, imidazole, DMAP, >98:2 d.r. (>98:2 e.r.) step and 88% yield ~0.7 g 32 ~1.7 g, DMF, 40 °C, 48 h from commercially (each batch; 2 batches) available alcohol CHO

35 67% overall yield (1.18 g)

– BF4 + NAd

Phosphine–Cu-catalysed Cu-boryl addn/EAA

OH

O Me

Me

Me

Me

OH

Rottnestol 67% overall yield (1.17 g)

5.0 mol% AdN

1. 31 (1.43 g), 10 mol% Pd(dppf)Cl 2, 1.5 equiv. Ba(OH) 2 •8H 2O, (pin)B DMF, 22 °C, 18 h 2. 5% aq. HCl, THF, 22 °C, 1.0 h

Figure 4 | Enantioselective gram-scale synthesis of rottnestol. Every stereochemical issue in the route is addressed by a catalytic process that involves an organoboron compound; this is highlighted by two multicomponent chemo-, site-, diastereo- and enantioselective assemblies. a, Site- and enantioselective NHC–Cu-catalysed B2(pin)2/allene/allylic phosphate and NHC–Ru-catalysed catalytic cross-metathesis (CM) reactions are combined to

9g

OH

O

Me

Me

OMe

Me

Me

OMe 36 93% yield, 97% , >98% E (1.81 g)

5.0 mol% CuCl 20 mol% NaOt-Bu, 1.1 equiv. B 2(pin) 2, 2.0 equiv. MeOH, THF, 22 °C, 12 h

access the acyclic fragment. b, A phosphine–Cu-catalysed multicomponent process involving an allene and an aldehyde is used to access the carbohydrate moiety. The final fragment coupling is achieved by phosphine–Pd-catalysed coupling, generating nearly 1.2 g of the natural product. DMAP, 4-dimethylaminopyridine; DMPU, N,N9-dimethyl-N,N9-trimethyleneurea; dppf, 1,19-bis(diphenylphosphino) ferrocene. Ad, adamantyl.

3 7 2 | N AT U R E | VO L 5 1 3 | 1 8 S E P T E M B E R 2 0 1 4

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ARTICLE RESEARCH OMe Me

•

OMe Me

OBOM

37 Prepared from (R)-methyl lactate in 7 steps and 29% overall yield in >98:2 d.r. and >98:2 e.r. (EtO) 2OPO 2b (1.5 equiv.)

5.0 mol% S-12d, 5.0 mol% CuCl 1.5 equiv. KOt-Bu, 1.5 equiv. B2(pin)2, THF, 50 °C, 18 h

Me

(pin)B 1

5

Me

Me OBOM

OMe

1. MeLi, THF, –78 0 °C, 1.0 h; I 2, MeOH,–78 0 °C, 1.0 h

Me 38 >98% conv., 76% yield >98% branched, >98% Z, >98:2 d.r. 3 batches; ~1.4 g 37 ~1.7 g each

(pin)B

Me Me

2. 5.0 mol% Ru complex 29, 1.2 equiv. vinyl–B(pin), CH2Cl2, reflux, 36 h

Me

Me

39 58% overall yield, >98:2 E,E (3.35 g)

OMe

O O CO2H

Me

Me

Me

Me Me

Herboxidiene/GEX1A 53% overall yield (1.03 g)

OH

1. BF3 •Et 2O, CH 2Cl2:Me 2S (2:1), –78 0 °C, 3.0 h 2. 20 mol% VO(acac ) 2, 3.0 equiv. t-BuOOH, CH2Cl2, –15 0 °C, 4.0 h; >98:2 d.r. 3. KOSiMe 3, THF, 22 °C, 2.5 h

Me O CO2Et

OMe Me

Me

Me

O I CO 2Et Me 40 Prepared in 8 steps, 32% overall yield, >98:2 d.r., >98:2 e.r. (2.02 g)

NHC–Cu-catalysed Cu-boryl addn/EAS

Me

OBOM

Me

Me

Me

OBOM

41 78% yield (2.55 g)

10 mol% Pd(dppf)Cl 2, 1.5 equiv. Ba(OH) 2•8H2O, DMF, 40 °C, 14 h

Figure 5 | Enantioselective gram-scale synthesis of herboxidiene. The key step, taking place at mid-point in the multistep route, involves a relatively complex enantiomerically pure monosubstituted allene (37). The reaction can be performed on gram-scale batches to obtain ,1.7 g of 1,5-diene 38 for each run (,76% yield), with .98% site-, Z- and diastereoselectivity. Subsequent conversion to E,E-diene 39 proceeds with complete stereochemical control as

well. Catalytic cross-coupling generates triene 41, which is then transformed to 1.03 g of the natural product. It is noteworthy that every transformation shown above that involves a stereochemical issue proceeds with complete selectivity (that is, catalytic multicomponent process, alkylation of the alkenylboron intermediate, catalytic cross-metathesis, catalytic cross-coupling and directed epoxidation). acac, acetylacetone.

stereoselectivity (.98:2 d.r. and e.r.). Ketone 34 was converted to carbohydrate 35 after four steps in 67% overall yield (1.18 g). NHC–Cu-catalysed protoboration of the terminal alkyne in 35 furnished b-alkenyl–B(pin) 36 in 97:3 b:a ratio, .98% E selectivity and 93% yield (1.8 g)41. More than one gram of stereoisomerically pure rottnestol was obtained after catalytic cross-coupling42 of alkenyl–iodide 31 and alkenyl–B(pin) 36 followed by generation of the cyclic hemiacetal by acid treatment. The route in Fig. 4 is more efficient than those reported previously (21.5% versus 3.7% overall yield)43 and which resulted in no more than milligram quantities of the target molecule.

and cost-effectively. Owing to the above features, and because the NHC– Cu-catalysed process is robust, gram quantities of a variety of complex organic molecules become reliably available. This advance foreshadows the development of protocols involving additional difficult-to-access alkenylboron-containing organocopper compounds. What emerges is the possibility of using other abundantly available poly-unsaturated hydrocarbons, such as dienes46 or enynes47,48, for efficient preparation of high-value products. Such a strategy obviates the need for succumbing to one-at-a-time installation of each functional unit, resulting in pathways that are unnecessarily time consuming, costly and waste generating.

Gram-scale total synthesis of herboxidiene Devising a route leading to anti-tumour agent herboxidiene was next. Here, we explored a different aspect of the NHC–Cu-catalysed transformation (Fig. 5). In the case of rottnestol, the multicomponent process was employed early on (27, Fig. 4); in contrast, with herboxidiene, the process would be implemented at a later stage with a more complex allene. In the event, ,7 g of substrate 37 were obtained by a seven-step procedure in 29% overall yield, .98:2 d.r. and e.r.; the central reaction in the sequence was phosphine–Cu-catalysed multicomponent reaction of B2(pin)2, methylallene 1c and an aldehyde derived from (R)-methyl lactate (compare synthesis of 34). Considerable structural complexity, including the appropriate 1,5-relative stereochemistry, was thus generated in short order: 1,5-diene 38 (,1.7 g for each run) was obtained in ,76% yield with complete site-, Z- and diastereoselectivity. Trisubstituted olefin 39 was accessed through alkylation and catalytic cross-metathesis with vinyl–B(pin), yielding ,3.3 g of the desired product; both alkenes were formed with .98% E selectivity. Phosphine–Pd-catalysed cross-coupling of alkenyl–B(pin) 39 with alkenyl-iodide 40, synthesized through a diastereo- and enantioselective eight-step process starting from b-(1)-citronellene (see Supplementary Information), afforded 2.55 g of triene 41. After three operations44,45, 1.03 g of the anti-tumour agent was secured; this represents an overall yield nearly twice that of the most concise of the previously reported syntheses45 (5.5% versus 3.4%; see Supplementary Information for bibliography).

Conclusions and discussions

Received 2 July; accepted 5 August 2014. 1. 2.

3.

4.

5.

6.

7. 8.

9.

10.

11.

The advances outlined here demonstrate that two simple unsaturated organic molecules and a commercially available diboron reagent can be combined to generate multifunctional alkenylboron fragments that are marked by several advantageous attributes. The requisite catalyst is assembled in situ by the reaction of abundant and inexpensive CuCl and a chiral ligand that is synthesized in multigram quantities readily

12. 13.

14.

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